Settable surgical implants and their packaging

ABSTRACT

The present invention relates to settable compositions for use in surgery. The invention also provides related compositions, including surgical kits and packages, as well as methods of making and using the settable compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/553,847, filed on Nov. 25, 2014 and claims priority to U.S.Provisional Application Ser. No. 61/909,140, filed on Nov. 26, 2013,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the field of medical implants,particularly settable, implantable compositions for medical use intissue hemostasis, repair and reconstruction and packaging for suchcompositions.

BACKGROUND

Biodegradable polymers have become increasingly important for a varietyof biomedical applications including biomedical implants, such asstents, and coatings applied to those implants, tissue engineeringscaffolds, and soft-tissue adhesives. Segmented polyurethane elastomersin particular have come into wide use as biomaterials due to theirsuperior mechanical properties and chemical versatility. PCTInternational Application Publication No. WO 2004009227 describescertain degradable polyurethane compositions for use as tissueengineering scaffolds. U.S. Pat. No. 6,306,177 (Felt et al.) describescurable polyurethane compositions comprising a plurality of partscapable of being sterilized, stably stored, and mixed at the time of usein order to provide a flowable composition upon mixing that issufficiently flowable to permit it to be delivered to the body byminimally invasive means. U.S. Patent Application Publication No.20050013793 (Beckman et al.) also describes degradable polyurethanes fore.g., tissue engineering and particularly for bone repair andreplacement. U.S. Pat. No. 4,829,099 (Fuller et al.) describes certainabsorbable polyisocyanates for use as surgical adhesives. U.S. Pat. Nos.8,002,843 and 7,985,414 (Knaack et al.) describe a biodegradablepolyisocyante (such as lysine diisocyanate) with an optionallyhydroxylated biomolecule to form a degradable polyurethane. U.S. Pat.No. 7,964,207 (Deslaurier et al.) describes osteoconductive polyurethanecompositions having mechanical properties consistent for use in bonerepair.

For certain applications, in addition to being biodegradable, it isadvantageous for a surgical implant to be moldable or formable, forexample to optimize its placement at the implant site and/or to fillvoids in hard or soft tissue at the site of implantation. U.S. Pat. Nos.8,431,147 and 8,282,953 (Warsaw Orthopedic, Inc) describe malleableimplants containing demineralized bone matrix. The “malleable implantcompositions” described in these patents contain a particulate solidcollagen material and a particulate solid DBM material along with aliquid carrier that comprises an aqueous gel of alginate. Alginate/DBMbased compositions are also described in U.S. Pat. No. 8,506,983 (WarsawOrthopedic, Inc). US 20130236513 (Guelcher et. al, Vanderbilt Univ.)describes polyurethane composites that, in some aspects, may be“processed” as a reactive liquid that subsequently cures in situ to forma solid composite.

SUMMARY OF THE INVENTION

The present invention provides compositions and methods relating tomoldable surgical implants suitable for use in hard and soft tissuerepair. In one embodiment, the compositions are particularly suitablefor use in bone repair, as bone void fillers, bone cements, and bonehemostats. In another embodiment, the compositions are suitable for softtissue repair, for example as soft tissue adhesives.

The compositions of the invention are provided in the form of a curableor settable composition comprising a plurality of component parts ofwhich are packaged separately, optionally sterile, and adapted to bemixed at the time of use to initiate a curing reaction. Preferably, thecomponent parts, once mixed, do not require a catalyst for curing. Theterms “settable” and “curable” are used interchangeably herein. In oneembodiment, the fully cured composition has mechanical propertiessuitable for drilling or accepting a surgical screw without shatteringor splintering. In one embodiment, the component parts of thecomposition are in the form of a putty or paste which is moldable,preferably hand-moldable, and in some embodiments sufficiently flowablefor extrusion, for example, from a syringe. The homogenous compositionformed from the mixture of the component parts is also in the form of aputty or paste which is moldable, preferably hand-moldable, and in someembodiments sufficiently flowable for extrusion, for a period of timeafter mixing and during curing. In one embodiment, the period of timefor complete cure into a hardened final form is from about 6 to 12 hoursor from about 6 to 24 hours. In one embodiment, the fully curedcomposition is drillable or machineable. In one embodiment, the settablecomposition cures into a final form that is thermoplastic and can besoftened to return it to a hand-moldable state by applying heatsufficient to warm the composition to a temperature at least higher than40° C., preferably between 40° C. and 100° C. In accordance with thisembodiment, where the composition sets or cures prematurely during use,it may be heated until it becomes moldable again for a period of timeuntil it cools. The compositions of the invention and their componentparts are preferably not in a low viscosity liquid form.

In one embodiment, the component parts each comprise an additive, suchas a colorant or dye, that imparts a color to the component. In oneembodiment, each component comprises a different colorant or dye suchthat when the component parts are combined to form the settablecomposition, the different colors mix to form a new color, which newcolor is also indicative that the composition has been mixed tohomogeneity. In one embodiment, the component parts can be mixed tohomogeneity within about 1 minute or less, or within about 2 minutes.

The invention also provides related compositions, including surgicalkits and packages, as well as methods of making and using the settablecompositions. In one embodiment, the invention provides a packagecomprising one or a plurality of settable compositions, each compositionconsisting of a set of two or more individual components, the componentsof a set comprising amounts of reagents which, upon mixing, react andcure into a final hardened form over a period of time, preferably atroom or body temperature. Each component is physically separated fromthe other components of the set within the package, and optionally, fromother sets of components. In one embodiment, the set consists of 2, 3,or 4 individual components. In one embodiment, the components aresterile. In one embodiment, the package is adapted to permit the removalof one set of components at a time while leaving the remaining sets in asealed, sterile, environment. In one embodiment, the package comprisesan upper peelable film configured to allow the exposure of one set ofputties at a time. In one embodiment, each component is physicallyseparated from the other components of its set within the package bymeans of a compartment or plurality of compartments in the package. In afurther embodiment, each set of components may optionally be separatedfrom other sets of the package by perforations allowing the set to beconveniently separated either before or after opening and removing thecontents.

In one embodiment, the plurality of compartments comprises depressionsor wells in a heat-sealable metal foil-based sheet. In one embodiment,the compartments of a set are flexible and separated by at least onebreakable seal adapted to allow the component putties of the set to bemixed together when the seal is broken. In one embodiment, thecompartments are in the form of one or more syringes, preferably one ormore foil-enclosed syringes. In one embodiment, the compartments are inthe form of a single syringe, preferably a foil-enclosed syringe,adapted to maintain individual component putties of a set separated fromeach other within the single syringe. In one embodiment, thecompartments are in the form of a plurality of syringes and each syringecontains a single component of a set. In one embodiment, eachcompartment comprises one or more surfaces in contact with an individualcomponent, the one or more surfaces comprising or consisting of a lowsurface energy material selected, for example, from the group consistingof polytetrafluoroethylene (PTFE), silicone, polypropylene,polyethylene, and polystyrene.

In one embodiment, the package further comprises an outer, heatsealable, preferably water impermeable or water resistant envelopecompletely surrounding the package, and a desiccant. In one embodiment,the outer envelope is a heat sealed, water impermeable or waterresistant foil package.

In one embodiment, the settable composition consists of a set ofcomponents, each in the form of a putty, that, upon mixing, react andcure into a polyurethane or polyureaurethane composition. In oneembodiment, at least one or at least two of the putty components of theset comprises an isocyanate component, a polyol/polyamine component, anda particulate component. In one embodiment, the particulate component ispresent in an amount of about 5-85 wt % based on the weight of the puttycomponent. In one embodiment, the particulate component is selected fromone or more of calcium sulfate, calcium phosphosilicate, sodiumphosphate, calcium aluminate, calcium phosphate, magnesium phosphate,hydroxyapatite, phosphate glass, biomimetic carbonate apatite, biphasiccalcium phosphate/hydroxyapatite, demineralized bone matrix, mineralizedbone, or non-resorbable metallic or polymeric materials, such aspolytetrafluoroethylene, polymethylmethacrylate, micronized titanium andpowdered stainless steel.

In one embodiment, the set consists of two putties, A and B, and theisocyantate component consists of a diisocyanate which is aromatic oraliphatic. Putty A comprises 15-40% of the isocyanate component, 0.5-5%of the polyol component, and 50-75% particulate material, based upontotal weight of Putty A; Putty B comprises 1-10% of the isocyanatecomponent, 3-15% of the polyol component, and 65-95% or 75-85%particulate material, based upon total weight of Putty B. In oneembodiment, the polyol in Putty A is present in a prepolymer with theisocyanate component such that there is substantially no unreactedpolyol in Putty A and the isocyanate component in Putty B is present ina prepolymer such that there is substantially no unreacted isocyanate inPutty B.

In one embodiment, the set consists of two putties, A and B. Putty Acomprises 15-40% of the isocyanate component, 0.5-5% of the polyolcomponent, and 40-85% particulate material, based upon total weight ofPutty A; Putty B comprises 1-10% of the isocyanate component, 3-15% ofthe polyol component, and 65-95% or 75-85% particulate material, basedupon total weight of Putty B.

In one embodiment, the set consists of two pastes, A and B. Putty Acomprises 15-40% of the isocyanate component, 0.5-5% of the polyolcomponent, and 50-75% particulate material, based upon total weight ofPutty A; Putty B comprises 1-10% of the isocyanate component, 3-15% ofthe polyol component, and 25-50% or 5-25% particulate material, basedupon total weight of Putty B.

In one embodiment, the set consists of two pastes, A and B. Putty Acomprises 15-40% of the isocyanate component, 0.5-5% of the polyolcomponent, and 40-85% particulate material, based upon total weight ofPutty A; Putty B comprises 1-10% of the isocyanate component, 3-15% ofthe polyol component, and 25-50% or 5-25% particulate material, basedupon total weight of Putty B.

The invention also provides methods for closing a wound by applying acomposition described herein to the wound in an amount sufficient toachieve wound closure.

The invention also provides methods for achieving hemostasis at a woundsite by applying a composition described herein to the bleeding wound inan amount sufficient to stop the flow of blood within a period of time,as described herein.

In one embodiment, the invention provides a biocompatible settablecomposition consisting of a plurality of component parts which, uponmixing, react to form a cured final composition at room or bodytemperature over a period time, the final composition optionally beingbiodegradable under physiological conditions. In one embodiment, theplurality of component parts consists of two parts, A and B, part Acomprising potassium dihydrogen phosphate or sodium phosphate dibasic,or optionally magnesium oxide and a calcium containing compoundsuspended in one or a mixture of anhydrous partially or completely watermiscible suspension vehicles and B comprises a viscosity building agentselected from one or more of a sodium, calcium or aluminumphyllosilicate or montmorillonite, a water absorbing clay, awater-absorbing polyacrylic acid, gelatin, sodium carboxymethylcellulose and hyprocellulose, and, optionally, a particulate materialselected from tricalcium phosphate, hydroxyapatite, or a mixturethereof. In one embodiment, the calcium containing compound is selectedfrom tricalcium phosphate and hydroxyapatite, or a mixture thereof. Inone embodiment, component B further comprises one or more additivesselected from a colorant, an antioxidant, and a therapeutic agent. Inone embodiment, the therapeutic agent is selected from one or more of ananticancer agent, an antimicrobial agent, an anesthetic agent, ananalgesic agent and an osteogenic agent. In one embodiment, eachcomponent of a set of two contains a different colorant selected fromprimary or secondary hues such that when the colored components aremixed, the colors combine to form a third color which may be used tovisually indicate homogeneity of the mixture. In one embodiment, thecomponents can be hand mixed to homogeneity in one minute, threeminutes, nine minutes, or twelve minutes. In one embodiment, one or moreindividual components contains an alkylpyrrolidone. In one embodiment,the first component is derived from a putty-like, concentrated aqueoussolution of an optionally crosslinkable polyanionic polymer and thesecond component derived from a putty-like concentrated solution of anoptionally crosslinkable polycationic polymer. In one embodiment, about0.1-5% graphene is added as a particulate component.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to curable or settable compositions foruse in surgery. The invention also provides related compositions,including surgical kits and packages, as well as methods of making andusing the settable compositions. The terms settable and curable are usedinterchangeably herein. The settable compositions described hereinconsist of at least two component parts that are provided as individualunits, each containing reagents in amounts such that when the componentsare combined they form a single homogenous composition that is settableand that reacts or cures into a final hardened form over a period oftime. In one embodiment, the mixture cures into a final hardenedcomposition at either room temperature or body temperature, over aperiod of time, and without the need to apply additional external heatin excess of the ambient heat of the room (about 24-26° C.) or the heatof the human body (about 37° C.). In one embodiment, the period of timefor complete cure into a hardened final form is from about 6 to 12 hoursor from about 6 to 24 hours. In one embodiment, the fully curedcomposition is drillable or machinable. In one embodiment, thehomogenous composition is thermoplastic and can be softened to return itto a hand-moldable state by applying heat sufficient to warm thecomposition to a temperature at least higher than 40° C., preferablybetween 40° C. and 100° C. In accordance with this embodiment, where thecomposition sets or cures prematurely during use, it may be heated untilit becomes moldable again for a period of time until it cools.

In one embodiment, the individual components are sterile.

In one embodiment, an optional chain extender, such as a diol ordiamine, or a crosslinker, such as a triol, polyol, triamine, orpolyamine is added to one of the component parts before combining, or tothe homogenous settable composition formed from the combining of thecomponent parts, in an amount sufficient to increase the rate of thecuring reaction.

In one embodiment, the component parts of a composition described hereare in the form of a putty or paste and may be combined, for example, byhand-kneading, or by extrusion, for example through a syringe, or byotherwise combining or compounding into a single homogenous composition.In one embodiment, the component parts each comprise an additive, suchas a colorant or dye, such that the additives impart a different colorto each component. In one embodiment, the separate additives, each of adifferent color, form a third new color when the components have beenmixed to homogeneity, such that the new color is indicates that a singlehomogenous composition has been formed. In one embodiment, the componentparts consist of part A and part B, part A comprises a colorant or dyewhich gives part A a red color, part B comprises a colorant or dye whichgives part B a blue color, and a composition of a substantially purplecolor is formed from the combination of parts A and B to homogeneity. Inone embodiment, the component parts can be mixed to homogeneity withinabout 1 minute or less, or within about 2 minutes.

In one embodiment, each component of a settable composition of theinvention is in the form of a putty and the homogenous settablecomposition that results from their combination is also in the form of aputty for a period of time after initiation of the curing reaction. Theterm “putty” refers to a composition that is soft, moldable, preferablynon-elastic, and cohesive.

In one embodiment, a putty is formed as a suspension or dispersion ofparticulates within a liquid. As an illustrative example of this generalform, one can consider the non-medical putty composition referred to asglaziers putty, which is diatomaceous earth or clay suspended in adrying oil such as linseed oil. In one embodiment of the presentinvention, the liquid components are selected from liquids such as thepolyol, chain extender and the polyisocyanate. Non-reactive, nontoxicorganic liquids such as esters, ethers and hydrocarbons may be employedin this context. In one embodiment, the solid components are particulatematerials selected from one or more of calcium phosphate, siliconizedcalcium phosphate, a substituted calcium phosphates where thesubstitution is with magnesium, strontium, or silicate, for example,calcium phosphosilicate, calcium pyrophosphate, hydroxyapatite,polyaryletherketone-based materials (e.g., PEK, PEEK, PEKK, PEEKK andPEKEKK), polyurethanes, polyureaurethanes, polymethylmethacrylate(PMMA), silicone polymers, glass-ionomer, absorbable phosphate glass,calcium sulfate, tricalcium phosphate (e.g., beta tricalcium phosphate),demineralized bone matrix (DBM), or mineralized bone, or any combinationof the foregoing.

In one embodiment, the particulate component for inclusion in acomponent part of the compositions described here is selected from oneor more of calcium sulfate, sodium phosphate, calcium aluminate,strontium phosphate, calcium strontium phosphate, tricalcium phosphate,calcium pyrophosphate, magnesium phosphate, hydroxyapatite, biomimeticcarbonate apatite, biphasic calcium phosphate/hydroxyapatite,mineralized bone matrix, demineralized bone matrix, glass ionomer,absorbable phosphate glass and nonresorbable particulate metallic orpolymeric materials such as stainless steel or titanium powder ornanoparticles, polyurethane, polyureaurethane, polymethacrylic acid andpolyarylether ketones such as PEK, PEEK, PEKK, PEEKK and PEKEKKparticles. Further examples of particulate materials are provided infra.

The particles of a particulate material used in the component parts ofthe compositions described here may be porous or non-porous particles.In one embodiment, the particles are porous and the degree of porosityis sufficient to permit the ingress of cells or fluids into thecomposition after its placement in situ. Particle size may also bevaried from about 0.05 to less than or equal to 1 millimeter or 2millimeters in diameter to control the consistency, with smallerparticle sizes yielding smoother more cohesive putties.

In one embodiment, the putty consistency is formed by the inclusion ofviscous prepolymers in at least one of the component parts of thecomposition. In this context, a prepolymer comprises reactive componentsthat are liquids and/or powders which are partially reacted by limitingone or more of the reactants to produce more viscous versions of theliquid components. Softeners such as nonreactive surfactants,hydrophilic compounds or polymers such as polyethylene glycol dialkylethers, etc., may also be added.

The settable compositions described herein are biocompatible andsuitable for use in vivo, particularly during surgery. The term“biocompatible” refers to materials that do not induce undesirableeffects when administered or implanted in vivo, for example, an immunereaction and/or an inflammatory reaction, or other adverse reaction thatis detrimental to wound healing and/or to the implant recipient. Abiocompatible material may also be referred to as “nontoxic”. In oneaspect, the biocompatible compositions described here form from alow-exotherm reaction and their formation does not produce toxic fumesor tissue-damaging amounts of heat. In another aspect, where thecompositions are biodegradable, their degradation under physiologicalconditions does not produce toxic by-products and/or is not toxic to theimplant recipient. In one embodiment, the maximum exotherm (amount ofheat i.e., temperature increase, generated by the reaction) of thepolymerization reaction is 20° C. or less, most preferably 10° C. orless.

In one embodiment, the compositions are fully or partiallybiodegradable. The terms “degradable”, “biodegradable”, “resorbable”,and “absorbable” are used interchangeably herein to refer to the abilityof the claimed compositions to degrade (partially or completely) underphysiological conditions into non-toxic products that can be metabolizedor excreted from the body within a period of time, generally severaldays and up to a year or about 18 to 24 months or longer. In oneembodiment, the composition is fully biodegradable within about 12months. Compositions may be considered non-biodegradable if they remainstable in vivo for periods exceeding about ten years.

In one embodiment, the compositions are osteopromotive or comprise anosteopromotive component. The term “osteopromotive” encompasses theability to support, enhance or accelerate the growth of new bone tissueby one or more of osteoconduction, and osteoinduction. In oneembodiment, the compositions further comprise one or more osteopromotiverecombinant proteins selected from the group consisting of bonemorphogenic proteins (e.g., BMP-2, BMP-7), platelet derived growthfactor, transforming growth factor beta, epidermal growth factor, NELLand UCB-1. In one embodiment, the osteopromotive component comprises anosteoconductive component. In one embodiment, the osteoconductivecomponent comprises or consists of particles of an osteoconductivematerial, such as particles of tricalcium phosphate or bioglass. Theterm “bioglass” refers to a group of glass-ceramic materials comprisingSiO₂, Na₂O, CaOP₂O₅, and combinations of these. Preferably, theparticles are in a size range of 1 micron to 2,000 microns average meandiameter.

In certain embodiments, a homogenous settable composition as describedhere is also mechanically hemostatic. In one embodiment, the homogenoussettable composition has the property of adhering to the surface ofactively bleeding bone with sufficient strength to stop the bleedingwithin at least about 1 minute, at least about 2-5 minutes, or at least5-10 minutes. In accordance with this embodiment, the homogenoussettable composition remains both moldable and sufficiently adhesive toadhere to the surface of actively bleeding bone for a period of timefollowing the combination of component parts that initiated the curingreaction. In one embodiment, the period of time is from about 1 to 30min, about 1 to 15 min, or about 1 to 10 min. It should be understoodthat characterizing the adhesive properties of the settable compositionduring a period of time after initiation of the curing reaction inrelation to bleeding bone is meant for descriptive purposes only, andnot intended to limit the use of the compositions to hard tissues. Insome embodiments, the settable compositions described here may also beuseful as soft-tissue hemostats. In addition, although the settablecompositions are described here as having physical properties suitablefor mechanical (tamponade) hemostasis, in certain embodiments ahemostatic composition of the invention may also contain one or moreagents that act as active chemical hemostats. Non-limiting examplesinclude blood clot-inducing agents such as prothrombin, thrombin,oxidized cellulose, microcrystalline collagen, gelatin foam, collagensponge, fibrinogen, and fibrin. In one embodiment, the composition mayalso comprise one or more of epinephrine, tannic acid, ferrous sulfate,and the double-sulfates of a trivalent metal and a univalent metal suchas potassium aluminum sulfate and ammonium aluminum sulfate. Thus, asettable composition may be hemostatic, mechanically or chemically, orby a combination of mechanical and chemical hemostasis.

Surgical Kits and Packages

The invention provides a surgical kit or package comprising a settablecomposition described herein. As discussed above, the settablecompositions described herein consist of at least two components thatare provided as individual units, each containing reagents in amountssuch that when the components are mixed, they react or cure into ahardened composition after a period of time, preferably at room or bodytemperature.

As a practical matter, during use of a settable composition in surgery,freshly made material may be required at widely spaced points in time.If the material is not mixed just before use, its moldability,uniformity, and adherence to the surfaces to which it is applied will bediminished. In this context, the adhesive nature of the material is afunction of its uncured state. In some embodiments, the composition asit cures bonds to the tissue at the site of implantation, for examplebone tissue. And if the material is compounded too early, it may setbefore it can be applied. In such a state it will be insufficientlymoldable, insufficiently adhesive, and unsuitable for use.

The surgical kits and packages described herein provide a solution tothis problem by providing the availability of freshly made settablematerial at different times during a surgical procedure.

In one embodiment, the present invention provides a container comprisingtwo or more compartments, each compartment containing an amount of acomponent. Where the container comprises multiple sets of components,the compartments are adapted such that each set can be removed withoutdisturbing the other sets in the package. If the components are sterile,the container is adapted such that each set of components can beaseptically removed without compromising the sterility of the remainingsets. For example, the separate compartments may form the lower part ofa vacuum-formed container with an upper peelable film. The constructionof the container allows for the removal of a single set of componentsfrom their respective compartments just before use. The components, thusexposed, then are removed from the container by a gloved finger or byusing an instrument and are kneaded together until homogenous to form asingle composition for surgical implantation. The composition thusformed will initially be in a moldable form. In one embodiment, thecomposition is in the form of a putty, and the components of each setare also in the form of putties. As the composition sets, it hardensinto a solid form. When needed, the next set of compartments in the unitis exposed by peeling down their covering film and kneading the newlyexposed putties together until homogeneous and ready for surgical use.In one embodiment, the container comprises pairs of compartments and theset of components is a pair. In one embodiment, the container comprises2 to 12 sets of components.

The compartments of the package may be, for example, in the form of adepression or well, or the compartments may comprise walls made of aflexible material having any shape, or an amorphous shape. In oneembodiment in which the package comprises multiple pairs of putties, thepackage may contain any desired number of putty pairs. In oneembodiment, the package consists of 2, 4, 8, 10, or 12 putty pairs. Inone embodiment, perforations may be placed between pairs to facilitateremoval of a pair before or after opening.

In one embodiment the package comprises separate compartments or wellsof a lower, vacuum-formed container with an upper peelable film,designed to allow a single set of putties to be removed from a singleset of compartments as needed, e.g., just before use during surgery. Inone embodiment, the set consists of two and a single package containsfrom 2 to 12 sets of putties.

In another embodiment, the package comprises a syringe component. In oneembodiment, the syringe component is a single syringe pre-loaded withmeasured amounts of a set of putties in separate internal compartmentsof the syringe such that when the syringe plunger is depressed, amountsof each component are dispensed or extruded from the syringe to form acomposition that will harden into a final solid (cured) form over aperiod of time at room temperature or body temperature. In oneembodiment, the syringe component comprises two or more syringes, eachpre-loaded with one component of a set. In one embodiment, the setconsists of two components.

In another embodiment, the package comprises separate flexiblecompartments within a flexible plastic container, each compartmenthaving a seal that, when disrupted, allows the contents of thecompartments to mix together into a common flexible plastic compartmentthat is configured to allow mixing of the contents within the commonflexible plastic compartment. In one embodiment, the package is flexibleenough to allow mixing by hand-kneading. In a further embodiment, aftermixing is complete, an orifice is cut into the container to allowremoval of the mixed components.

In one embodiment, the package comprises or consists of a heat sealed orheat sealable foil package. In one embodiment, the package furthercomprises an outer envelope completely surrounding the package, and adesiccant. In one embodiment, the outer envelope is a heat sealed,pinhole free foil package.

In one embodiment, the package comprises a surface which is in contactwith the components, said surface having a surface energy substantiallyequal to or less than the surface energy of the components, or both,such that the component does not adhere or adheres weakly to thesurface. In one embodiment, the surfaces of the package that are incontact with the components are coated with a surface having a surfaceenergy substantially equal to or less than the surface energy of thecomponents such that they do not adhere, or adhere weakly to, thesurface. In one embodiment, the surface is formed of a material selectedfrom the group consisting of polytetrafluoroethylene (PTFE), silicone,polypropylene, polyethylene, and polystyrene.

In certain embodiments, a package has a shelf life of at least 1-2years. In certain embodiments, the package has a shelf life of 6 months,12 months, 18 months, 24 months, or 36 months.

The invention also provides a method for making a settable composition,the method comprising the steps of providing a package as describedherein, the package containing a single set or multiple sets ofcomponents which, when mixed together, cure into a final hardenedcomposition, and mixing a set of components into a homogenous mass. Inanother embodiment, the method comprises the steps of extruding measuredamounts of a set from one or more syringes and kneading them together toform a single homogenous mass which cures into a final hardenedcomposition. In one embodiment, the method comprises the steps ofproviding a package comprising a set of components in separate flexiblecompartments within a flexible container, the compartments having abreakable seal that, when broken, allows the contents of the compartmentto enter into a further flexible compartment, breaking the seal suchthat the set of components enters into the further compartment, mixingthe components into a homogenous mass within the further compartment.

As an aid to manipulating the components after extrusion from thesyringe or syringes, or after removal from the packaging of theinvention, the surgeon may employ a device having a pliable structurewith an application surface having a surface energy substantially equalto or less than the surface energy of the composition such that thecomposition does not adhere or adheres very weakly to the device. Thedevice is preferably in the form of a sheet. Suitable materials forforming the application surface include, for example,polytetrafluoroethylene (PTFE), silicone, polypropylene, polyethylene,and polystyrene. Such devices are described in US 2012/0035610.

The compositions, packages and methods of the invention are for use insurgical procedures. Preferably, the surgical procedures are practicedon humans, but they may also be used on other mammals such as a dog, acat, a horse, a cow, a pig, or a non-human primate. In one embodiment,the surgical procedure is a procedure for the repair of cranial defectsand cranioplasty applications or for repair and reconstruction of thesternum. In one embodiment, a composition as described herein issuitable for use as a tissue adhesive, a hemostat, a bone cement, or abone void filler.

In one embodiment, a composition, as described herein, is suitable foran orthopedic application as a bone hemostat, a bone adhesive, a bonevoid filler, or a bone cement. The term “bone cement” is meant todistinguish related surgical implants, such as soft tissue adhesives,which may not possess the mechanical properties suitable for use in bonerepair. A bone cement composition, when fully cured, has compressivestrength, tensile strength, and elasticity suitable for use in bonerepair or reconstruction. The solid form also bonds to bone or suitablemetal surfaces and reaches a supporting bond strength within about 90minutes and fully cures within about 24 hours. The solid form furtherbonds with tensile and shear strength comparable with normal bone withinabout 72 hours. In one embodiment, the mixture of putties fully curesinto its solid form at room temperature or body temperature within about90 minutes or about 120 minutes.

In one embodiment, the fully cured composition is suitable for use inbone repair or as a bone cement or bone void filler and has acompressive strength of from 30 to 150 MPa, or greater, a tensilestrength of from 20 to 80 MPa, or greater, and an elasticity defined bya Modulus of Elasticity of from 1,400 to 1,800 MPa, or greater. Incertain embodiments, the compressive strength is at least 30 MPa, atleast 40 MPa, at least 50 MPa, at least 60 MPa, at least 70 MPa, atleast 80 MPa, or at least 100 MPa. In some embodiments, the compressivestrength is greater than 100 MPa or greater than 150 MPa. In oneembodiment, the compressive strength is between 100 and 150 MPa orbetween 150 and 200 MPa. Preferably, the solid form is sufficientlydurable to be drillable or machineable. In certain embodiments the solidform has a tensile strength of at least 20 MPa, at least 30 MPa, atleast 40 MPa, at least 50 MPa, at least 60 MPa, or at least 80 MPa. Incertain embodiments the solid form has a Modulus of Elasticity of atleast 1,400 MPa, at least 1,500 MPa, at least 1,600 MPa, or at least1800 MPa. In one embodiment, the solid form has a compressive strengthof at least 60 or 70 MPa, a tensile strength of at least 40 or 50 MPa,and an elasticity of at least 1,600 or 1,800 MPa.

In one embodiment, the fully cured composition is suitable for use insoft tissue and has a compressive strength of from 0 to 25 MPa, from 0to 10 MPa, or from 0 to 5 MPa, and a tensile strength of from 0.005 to80 MPa, or from 0.005 to 20 MPa, or from 0.005 to 15 MPa. In certainembodiments, the compressive strength is less than 30 MPa, less than 25MPa, less than 20 MPa, less than 10 MPa, or less than 5 MPa.

The mechanical properties described here refer to the properties of thecomposition alone, without the addition of other, optional, materialswhich may further increase these physical properties, especiallycompressive strength. In one embodiment, the compositions of theinvention do not comprise an optional particulate material. In certainembodiments, the particulate material, if present, is present in anamount up to about 80% by weight of the composition.

In one embodiment, the compositions are fully or partially degradableunder physiological conditions within a period of time. Where thecompositions are fully degradable, they are degraded within about 12months. The degradation may be enzymatic or non-enzymatic or acombination of both. In one embodiment, the compositions of theinvention are initially degradable into non-toxic products by anon-enzymatic hydrolysis under physiological conditions. In a preferredembodiment, the compositions are fully degradable within a period oftime less than 12-24 months. In certain embodiments, the polymerdegradation time does not exceed 3 months or 6 months. In oneembodiment, a composition of the invention is degradable within about 2to 4 weeks after placement in vivo. In other embodiments, a compositionof the invention is fully degradable within about 4 to 6 weeks, orwithin about 2 to 4 months, 4 to 6 months, 6 to 8 months, or 8 to 12months. In certain embodiments, the compositions comprise componentsthat are fully degradable or absorbable. In other embodiments, thecompositions are comprised of components that are partially degradableor absorbable, or non-degradable. In certain embodiments, thecompositions are formed from a combination of fully degradable,partially degradable, and/or non-degradable components.

Cyanoacrylate- and Methylidene Malonate Ester-Based Compositions

In one embodiment, the settable composition of the invention consists ofat least two components that, when mixed together, form a mixture thatcures into a fully hardened polymer composition comprising eithermethylidene malonate or alkyl cyanoacrylate esters such as octylcyanoacrylate polymers. The first component comprises, for example,either diethylmethylidene malonate or octyl cyanoacrylate monomer, aviscosity builder such as a minor amount of poly(diethylmethylidinemalonate) or poly(octylcyanoacrylate), a free radical polymerizationinhibitor component, e.g., hydroquinone, an acid component to inhibitbased-catalyzed polymerization, e.g., sulfur dioxide and an optionalanhydrous particulate component. The one or more additional componentscomprise the viscosity builder of the first component and, optionally, aparticulate material, and one or more additional optional additives. Inone embodiment, the one or more additional optional additives areselected from a colorant, a therapeutic agent and a radiopaque agent

The one or more additional components may further comprise an optionaltherapeutic agent. In one embodiment, the therapeutic agent is selectedfrom one or more of an anti-cancer agent, an antimicrobial agent, anantibiotic, a local anesthetic or analgesic, and an anti-inflammatoryagent.

In one embodiment, the one or more additional components may furthercomprise a bone-growth promoting agent. In one embodiment, the bonegrowth promoting agent is selected from bone morphogenic protein anddemineralized bone matrix, and mixtures thereof. In one embodiment, thebone-growth promoting agent is an osteopromotive recombinant proteinselected from the group consisting of bone morphogenic proteins,platelet derived growth factor, transforming growth factor beta,epidermal growth factor, NELL and UCB-1, and combinations thereof.

In one embodiment, the composition comprises two putty components, A andB; and putty A comprises 20-50% of the diethylmethylidene malonate oroctyl cyanoacrylate monomer, 1-15% of the viscosity building component,0-75% particulate material, based upon total weight of putty A, aradical polymerization inhibitor component and an acidic polymerizationinhibitor component; putty B comprises 3-40% of the viscosity buildingcomponent, and, optionally, 0-85% of particulate material, based uponthe total weight of putty B, and one or more optional therapeutic agentsor growth promoting agents. In one embodiment, the viscosity buildingcomponent comprises polymerized monomer, the radical inducedpolymerization inhibitor component comprises or consists of hydroquinoneand the acid induced polymerization inhibitor component comprises orconsists of sulfur dioxide.

Magnesium Phosphate-Based Compositions

In one embodiment, the settable composition of the invention consists ofat least two components that, when mixed together, form a mixture thatcures into a fully hardened non-polymeric composition. The firstcomprises potassium dihydrogen phosphate, magnesium oxide, and a calciumcontaining compound such as, e.g., tricalcium phosphate and/orhydroxyapatite (Ca₁₀(PO₄)₆(OH)₂. The first component suspended in one ora mixture of anhydrous, nontoxic, partially water-miscible, inertsuspension vehicles, for example one or a mixture of two or more oftriacetin, a Pluronic (poloxamer) such as Pluronic L-35, and acetyltriethyl citrate, or similar liquids. A nontoxic viscosity buildingagent may be added, if necessary. The one or more second componentcomprises water, and one or a mixture of two or more viscosity buildingagents. In one embodiment, the viscosity building agent or agents areselected from sodium carboxymethyl cellulose, sodium alginate, Carbomer,carrageenan, aluminum silicate (Bentonite), gelatin, collagen, andchitosan. In one embodiment, the viscosity building agent is present atabout 75-85 wt %. The second putty component may also optionallycomprise a particulate material. In one embodiment the particulatematerial is selected from tricalcium phosphate and hydroxyapatite, ormixtures thereof. In one embodiment, the one or more additional secondcomponents may also optionally comprise one or more additional additivesselected from a colorant, an antioxidant, and a therapeutic agent, forexample, a statin.

In one embodiment, the therapeutic agent is selected from one or more ofan anti-cancer agent, an antimicrobial agent, an antibiotic, a localanesthetic or analgesic, a statin and an anti-inflammatory agent. In oneembodiment, the one or more additional component putties may furthercomprise a bone-growth promoting agent.

In one embodiment, the composition comprises two putty components, A andB, putty A comprising a methylidene malonate ester and apoly(methylidene malonate ester) in amounts ranging from 30 to 70% andputty B comprising poly(methylidenemalonate ester), in amounts rangingfrom 30 to 100%, wherein the amounts are based upon total weight of thecomposition.

In one embodiment, the composition comprises two putty components, A andB, putty A comprising or consisting of a cyanoacrylate ester in amountsranging from 30 to 70% and a poly (cyanoacrylate) ester in amountsranging from 70 to 30% and putty B comprising poly(cyanoacrylate) esterin amounts ranging from 97 to 100%, wherein the amounts are based upontotal weight of the composition.

Isocyanate-Based Compositions

In one embodiment, the settable composition of the invention consists ofat least two component parts, A and B, that when combined form acomposition that cures into a fully hardened polymeric composition, thepolymer selected from a polyurethane, a polyureaurethane, apolyetherurethane, or a polyesterurethane, over a period of time at bodytemperature (i.e., about 37 C). At least one of the component partscomprises an isocyanate component and one or both component partscomprise a polyol/polyamine component. The isocyanate component consistsof an isocyanate monomer, polymer, prepolymer, or combination thereof.The isocyanate component may thus comprise one or more differentisocyanates, as well as an isocyanate in both its monomeric form and itspolymer or prepolymer form. The term “isocyanate” is used generically torefer to isocyanates, diisocyanates, and polyisocyanates. The term“polyol” in the context of the “polyol/polyamine component” refers toboth diols and polyols. Thus, the polyol or polyamine component maycomprise or consist of one or more different diols, polyols, polyamines,or mixtures of two or more diols, polyols and/or polyamines.

In one embodiment, the composition further comprises an additiveselected from one or more of tocopherol esters (e.g., tocopherylacetate), triglycerides, acetyl triethyl citrate, and fatty acid esters,to aid in handling properties and packaging. In one embodiment, thecomposition further comprises one or more additives selected from anantioxidant, an anhydrous particulate material, a colorant, atherapeutic agent, and a radiopaque agent. In one embodiment, thetherapeutic agent is selected from one or more of an anticancer agent,an antimicrobial agent, an anesthetic agent, an analgesic agent, ananti-inflammatory agent, and an osteogenic agent.

In one embodiment, the composition further comprises an osteoconductivecomponent. In one embodiment, the osteoconductive component also confersporosity to the composition and the porosity is sufficient to allow theingress of fluids and/or cells (e.g., osteoclasts, blood cells) into thecomposition in situ. In one embodiment, the osteoconductive componentcomprises or consists of particles of an osteoconductive material, suchas particles of tricalcium phosphate or bioglass. The term bioglassrefers to a group of glass-ceramic materials comprising SiO₂, Na₂O,CaOP₂O₅, and combinations of these.

In one embodiment, porosity is not introduced into the composition as itcures by the addition of water or a carboxylic acid, e.g., benzoic acid,into any of the component parts of the composition. In one embodiment,the component parts do not contain either a carboxylic acid or addedwater such that the only water present during the curing reaction iswater that may optionally be present at the site of implantation in thebody.

In one embodiment, the fully hardened polyurethane or polyureaurethanecomposition possesses sufficient mechanical properties to be weightbearing, for example for use as a weight-bearing implant in bone, suchas a bone void filler, or a bone cement.

In one embodiment, one or more of the components of the compositioncomprises a prepolymer. A prepolymer is a polymer having reactive endgroups, e.g., isocyanate or hydroxyl groups. In one embodiment, theprepolymer comprises an excess of the isocyanate component relative tothe polyol/polyamine component. In one embodiment of a two-componentcomposition, one component comprises a prepolymer and no, orsubstantially no, unreacted polyol; and the second comprises or consistsof a hydroxyl terminated prepolymer lacking free isocyanate groups andunreacted polyol or polyamine.

A low molecular weight polymer refers to a polymer having a numberaverage molecular weight in the range of about 500 to 20,000 or 500 to10,000. A prepolymer containing reactive isocyanate end groups isformed, for example, from the initial reaction of an excess ofisocyanate with a limiting amount of polyol or polyamine

Each of the components may also independently comprise an optionalparticulate material and an optional chain extender, crosslinker, orcurative.

As discussed above, the components of the settable composition areprovided as individual units, each containing reagents in amounts suchthat when the components are mixed together, they form a mixture thatfully reacts or cures into a hardened composition after a period of timeat room or body temperature. For example, where the settable compositioncomprises two putties, A and B, putty A comprises an excess of theisocyanate component relative to the polyol component and putty Bcomprises less of the isocyanate component and more of thepolyol/polyamine component than putty A. Putty B also optionallycomprises a chain extender and/or crosslinker. Each putty optionallycontains an amount of particulate material suspended in the liquidcomponents to form a composition having a putty-like consistency.

In one embodiment, the particulate material is selected from one or moreof a polyurethane, calcium sulfate, calcium phosphosilicate, sodiumphosphate, calcium aluminate, calcium phosphate, hydroxyapatite,demineralized bone, or mineralized bone. Other particulate materials mayalso be used, as described infra.

In one embodiment, putty A comprises 15-50% of the isocyanate component,0.5-5% of the polyol component, and 40-75% particulate material, basedupon total weight of putty A; putty B comprises 1-10% of the isocyanatecomponent, 3-15% of the polyol component, and 65-85% particulatematerial, based upon total weight of putty B.

In one embodiment, putty A comprises 20-35% of the isocyanate component,0.5-5% of the polyol component, and 50-75% particulate material, basedupon total weight of putty A; putty B comprises 1-10% of the isocyanatecomponent, 3-15% of the polyol component, and 75-85% particulatematerial, based upon total weight of putty B.

The Isocyanate Component

In one embodiment, the isocyanate component comprises or consists of anaromatic isocyanate, an aliphatic isocyanate, a cycloaliphaticisocyanate, or an adduct of an isocyanate, or a mixture of any of theforegoing. A mixture refers to a mixture of two or more of theforegoing. For example, the isocyanate component may comprise or consistof a mixture of two or more isocyanates independently selected from anaromatic isocyanate, an aliphatic isocyanate, a cycloaliphaticisocyanate, and an adduct of an isocyanate.

In one embodiment, the isocyanate is an aliphatic isocyanate selectedfrom the group consisting of ethyl lysine diisocyanate, hexamethylenediisocyanate, cyclohexyl diisocyanate.

In one embodiment, the isocyanate component comprises one or moreisocyanates that are relatively non-absorbable. In one embodiment, theisocyanate is an aromatic isocyanate selected fromdiphenylmethanediisocyanate (MDI), including mixtures thereof such asmixtures of 2,4′-diphenylmethanediisocyanate and4,4′-diphenylmethanediisocyanate isomers (ISONATE 50 OP, Dow ChemicalCo. and RUBINATE 9433, Huntsman Corp.) and its pure4,4-diphenylmethanediisocyanate form (MONDUR M, Bayer AG and RUBINATE44, Huntsman Corp.). In one embodiment, the aromatic isocyanate is oneof the commercially available polymeric isocyanates ISONATE 143L,ISONATE PAPI 901, and ISONATE PAPI 27 (Dow Chemical Co.). Theseisocyanates, particularly the diphenylmethane derivatives, generallyresult in non-absorbable or slowly absorbable polyurethanes.

In one embodiment in which the composition is fully or partiallyabsorbable, the isocyanate component comprises or consists of[5-[2-[2-(4-Isocyanatobenzoyl)oxypropanoyloxy]-ethoxy]-1-methyl-2-oxo-pentyl]-4-isocyanatobenzoate,or “ALD”. In one embodiment, the two lactyl moieties of ALD each areracemic. Alternatively, these lactyl moieties may both have D or the Lconformations. Alternatively, one lactyl moiety may be D while the otheris L, or one may be D, L while the other is D or L. Such changes instereochemistry may improve the physical and/or biological properties ofthe resulting polymer.

In one embodiment, the adduct of an isocyanate is selected from ahexamethylene diisocyanate trimer (DESMODUR N-3390) and a hexamethylenediisocyanate biuret (DESMODUR N-100) both commercially available fromBayer AG.

In one embodiment, the settable composition, which may be formed from apolymer selected from a polyurethane, a polyureaurethane, apolyetherurethane, or a polyesterurethane comprises at least onehydrolysable linkage. In one embodiment, the at least one hydrolysablelinkage is derived from glycolic acid, lactic acid, caprolactone, orp-dioxanone. In one embodiment, the at least one hydrolysable linkage isselected from the group consisting of ester, amide, anhydride andsulfonamide linkages between the ester-urethane, urethane- orureaurethane-containing groups. In one embodiment, the compositioncomprises one or more glycolyl, lactyl, or caprolactyl hydrolysableester linkages. In one embodiment, the composition comprises one or moreethylene glycol, diethylene glycol, propane diol or butane diolhydrolysable ester linkages. In one embodiment, the compositioncomprises one or more ethylene diamine, propane diamine, butane diamine,hexamethylene diamine and polyalkylene diamine hydrolysable amidelinkages. In one embodiment, the composition comprises one or morelactyl hydrolysable ester linkages and each asymmetric lactyl moietypresent in the polymer is selected from one or more of the D, the L orthe DL (racemic) stereoisomers.

The hydrolysable isocyanate based compositions are degradable at leastdue to the presence of functional groups in the polymer chain that arereadily hydrolysable under physiological conditions. Thus, the term“partially degradable” as used in the present specification encompassesthe percentage of functional groups in the polymer chain that arehydrolyzed compared to the total number of hydrolysable groups. In thiscontext, a partially degradable isocyanate based composition encompassescompositions in which, after a suitable period of time, about 75% of thehydrolysable groups are hydrolyzed. In certain embodiments, a partiallydegradable compositions is one in which about 25% to 75% or 50% to 75%or about 75% to 90% of the hydrolysable groups are hydrolyzed.

The rate of degradation of the compositions can be controlled in orderto provide compositions that degrade at a slower or faster rate,compared to a base composition. In general, the rate of degradation iscontrolled by varying the isocyanate and polyol/polyamine components ofthe compositions, as well as the optional chain extender componentaccording to the following parameters. In one aspect, the rate ofdegradation is controlled by choice of the isocyanate and polyol.Generally, the more hydrolysable linkages, the faster it will degradewhile less hydrolysable linkages will degrade slower. In another aspect,the rate of degradation is controlled by varying thehydrophobic/hydrophilic balance of the polyol/polyamine component.Generally, the more carbon atoms or methylene groups between thehydrolysable functions, the slower will be the hydrolysis. For example,ethylene glycol will provide a composition that hydrolyses more rapidlythan, for example, 1,3 propane diol, which in turn hydrolyses morerapidly than 1,4 butane diol. In addition, the use of hydrolysablediamines as chain extenders may increase the rate of hydrolysis. Inanother aspect, copolymers of caprolactone and glycolide hydrolyzefaster than copolymers of caprolactone and lactide and the addition ofD, L-lactide also increases the rate of hydrolysis. Thus, for example, abis-diphenyldiisocyanate bridged with a polyglycolide, apolyglycolide-co-lactide, a polylactide, apolycaprolactone-co-glycolide, a polycaprolactone-co-lactide, apolycaprolactone will hydrolyze at increasingly slower rates. Forcomparison, polyurethanes prepared using methylenebis-diphenyldiisocyanate, with no hydrolyzable linkages, are notsignificantly degradable under physiological conditions. In otherembodiments, enzymatic sensitive sites such as di or polylysines orarginines are incorporated into one or more of the substituents. Inanother embodiment, the polyol or polyamine component, e.g.,hydroxymethylglycolate, may have a hydrolysable linkage to increase therate of degradation,

In one embodiment, the isocyanate component comprises a polyaromatic di-or polyisocyanate having at least one hydrolysable linkage bridging atleast two of the aromatic rings. In certain embodiments, thehydrolysable linkage bridging the aromatic rings is derived fromglycolic acid, lactic acid, caprolactone, or p-dioxanone. In most cases,the hydrolyzable linkage is an ester which may degrade into an acid andan alcohol as a result of exposure to water or to naturally occurringesterases. Amide linkages are usually more difficult to hydrolyze thanesters. Another option is the easily hydrolyzable acid anhydridelinkage. Sulfonamides may also be considered in this context. Thepolyaromatic di- or polyisocyanates described herein are distinct fromisocyantes having only a single aromatic ring such as toluenediisocyante, methylene bis-p-phenyl diisocyanate, and aromaticpolyisocyanates generally. Suitable isocyanates are described in U.S.Pat. No. 7,772,352 and U.S. Patent Application Serial No. 2009/0292029,each of which is incorporated herein by reference.

In certain embodiments, the fully cured isocyanate based compositionshave a defined pore size. Porosity may be controlled through theinclusion of water, surfactants, and/or cell openers during the processof combining the one or more isocyanate components with thepolyol/polyamine component to form the isocyanate based compositions.For example, porosity may be controlled by the addition of a smallamount of water to a prepolymer containing isocyanate groups. The waterreacts with the isocyanate group to form carbon dioxide, resulting inporosity.

In one embodiment, the solid form has an average pore size in the rangeof from about 5 to 700 microns. In certain embodiments, the average poresize is from about 5 to 100 microns, from about 5 to 300 microns, fromabout 5 to 500 microns, and from about 5 to 700 microns. In certainembodiments, the average pore size is from about 100 to 300 microns,from about 200 to 500 microns, from about 300 to 600 microns, and fromabout 500 to 700 microns, or greater.

In another embodiment, the solid form has an average pore size in thesubmicron range. In certain embodiments, the average pore size is fromabout 100 to 1000 nanometers, from about 100 to 400 nanometers, fromabout 400 to 800 nanometers, from about 200 to 600 nanometers, or fromabout 500 to 900 nanometers.

Porosity may also be introduced into through the use of porous fillermaterials (e.g., commercially available calcium phosphates with poresizes of 200 microns or greater).

In one embodiment, the isocyanate based compositions are formed from anisocyanate component that comprises or consists of a glycolide-linkedpolyaromatic diisocyanate monomer and a polyol component that comprisesor consists of a polycaprolactone-co-glycolide polyol. In oneembodiment, the isocyanate based compositions are formed from a reactionthat also comprises butanediol, e.g., as a chain extender. In oneembodiment, the composition is formed from a reaction that furthercomprises one or more of water, a carboxylic acid, e.g., benzoic acid(as a foaming agent), a divalent or polyvalent metal salt, a metalcarbonate or bicarbonate, or a phosphate, e.g., for osteoconductivity.In one embodiment, the glycolide-linked diisocyanate monomer has thefollowing structure:

In one embodiment, the polycaprolactone-co-glycolide polyol has thefollowing structure:

-   -   [HOCH₂CO₂CH₂CH₂CH₂CH₂CO₂CH₂OH]_(n)

In one embodiment, the isocyanate based compositions are formed from anisocyanate component that comprises or consists of a lactide linkeddiisocyanate monomer and a polyol component that comprises or consistsof a polycaprolactone-co-lactide polyol. In one embodiment, theisocyanate based compositions are formed from a reaction that alsocomprises butanediol, e.g., as a chain extender. In one embodiment, thecomposition is formed from a reaction that further comprises one or moreof water, a carboxylic acid, e.g., benzoic acid (as a foaming agent), adivalent or polyvalent metal salt, a metal carbonate or bicarbonate, ora phosphate, e.g., for osteoconductivity. In one embodiment, thelactide-linked diisocyanate monomer has the following structure:

In one embodiment, the polycaprolactone-co-lactide polyol has thefollowing structure:

-   -   HO[CH(CH₃)CO₂CH₂CH₂CH₂CH₂CO₂CH(CH₃)]OH_(n)        The Polyol/Polyamine Component

The diols, polyols, and polyamines suitable for use in formingabsorbable polyurethane-based compositions are either degradable ornon-degradable, or a mixture of the two. As used herein, the term“polyol” is meant to refer generically to diols and polyols, unlessindicated otherwise. Generally, absorbable isocyanate based compositionsare formed by the combination of an excess of the isocyanate componentwith the polyol/polyamine component. The relative amounts are calculatedas the molar ratio of NCO groups of the isocyanate component (I) to theactive hydrogen functional groups (H) (e.g., hydroxyl, amino, andmixtures thereof) of the polyol/polyamine component. Generally, theratio of polyisocyanate to polyol/polyamine (I:H) is at least 0.5:1. Incertain embodiments, the ratio is about 1:1, about 1.5:1, about 2:1,about 3:1, or about 4:1. In other embodiments, the ratio is about 5:1,about 8:1, about 10:1, about 20:1, or about 50:1.

In certain embodiments, the polyol/polyamine component is present in anisocyanate prepolymer in an amount of from about 0.5% to about 50% byweight of the prepolymer. In certain embodiments, the polyol/polyaminecomponent is present in an amount of from about 0.5% to 10%, from about10% to 20%, from about 20% to 35%, from about 25% to 40%, or from about35% to 50% by weight of the prepolymer.

Polyols suitable for use include biocompatible, naturally occurringpolyols, synthetic polyols, and mixtures thereof. In certainembodiments, the polyols comprise at least one ester group. In certainembodiments, the polyol comprises 2 to 4 ester groups or 5 to 10 estergroups. In one embodiment, the polyol has two or more hydroxyl groups.Suitable polyols include diols and polydiols having repeating unitscontaining up to about 18 carbon atoms. Examples of suitable diolsinclude 1,2-ethanediol (ethylene glycol), 1,2-propanediol (propyleneglycol), 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol,1,3-cyclopentanediol, 1,6-hexanediol, 1,8-octanediol and combinationsthereof. Examples of preferred polydiols include polyethylene glycolwith molecular weights of from about 500 to about 10000,polytetramethylene ether glycols, polyols derived from glycolide,lactide, trimethylenecarbonate, p-dioxanone and/or caprolactone withmolecular weights of about 500 to about 10000.

In one embodiment, one or more alkylpyrrolidones (see e.g., U.S. Pat.No. 7,955,616) may be added to the polyol component to improve healing.

In one embodiment, the polyol is a synthetic polyol selected from apolycaprolactone polyol, polyester polyols, polyadipate polyols (e.g.,poly(hexane-adipate) diol, poly(butane-adipate) diol,poly(ethylene/propylene-adipate) diol, poly(hexane/adipate/isophthalatediol)), and polyols that have been derived from a synthetic acid (e.g.,isophthalic acid, maleic acid). An example of a suitable biocompatiblesynthetic polyol is a polycaprolactone diol that is commerciallyavailable from Dow Chemical under the trade name TONE 32 B8. apolycaprolactone co-glycolide or a polycaprolactone co-lactide. Furthernon-limiting examples of suitable synthetic polyols includepoly(oxypropylene) glycols, poly(oxytetramethylene) glycols, andpoly(oxyethylene) glycols. In one embodiment, the synthetic polyol isselected from a polycaprolactone co-glycolide or a polycaprolactoneco-lactide.

In one embodiment, the polyol is a naturally occurring polyol selectedfrom castor oil and lesquerella oil, the polyols that may be obtained bychemical modification of naturally occurring vegetable oils (e.g.,castor oil, olive oil, sesame oil, corn oil), naturally occurring oilsthat have been trans-esterified (e.g., a modified castor oil polyol thathas been prepared by the transesterification reaction of natural castoroil with suitable crosslinkers (e.g., glycerol, trimethylolpropane, andthe like) or with acids (such as adipic acid), and naturally occurringoils that have been hydrogenated. Further non-limiting examples ofsuitable naturally occurring polyols include the commercially availablecastor-oil-based polyols CASPOL5001, CASPOL1962, and CASPOL5004 (allavailable from CasChem, Inc.). In certain embodiments, the polyol is nota naturally occurring polyol such as castor oil and lesquerella oil.

In certain embodiments, an isocyanate prepolymer is combined with apolyamine to form a poly(urethane-urea). The polyamine may be a primaryor secondary di-amine, or a hindered amine. Non-limiting examples ofsuitable polyamines include, hindered diamine (e.g., isophorone diamine,“IPDA”), 1,4-cyclohexyl diamine, 1,3-pentane diamine, and aliphaticsecondary diamines, and mixtures thereof. In certain embodiments of thepresent invention, aliphatic diamines and cycloaliphatic diamines may beparticularly suitable, and may offer improved biocompatibility.Commercially available examples of suitable polyamines include CLEARLINK1000 (Dorf Ketal).

Amines including diamines that may be suitable for use in thepreparation of polyurea and polyureaurethanes include but are notlimited to polyethyleneimines, PEG amines with weight average molecularweights from about 500 to about 5,000, polyoxypropylenediaminesavailable under the tradename JEFFAMINES (Huntsman Corporation, Houston,Tex.) and polyetherdiamines in general, spermine, spermidine,hexamethylenediamine, octamethylenediamine, decamethylenediamine,dodecamethylenediamine, hexadecamethylenediamine,octadecamethylenediamine, polyamidoamine dendrimers, dextrans,PEG-dextran conjugates, cysteines, proteins and peptides containingamines, non-biologically active symmetrical and asymmetrical diaminocompounds containing saturated and unsaturated, substituted andunsubstituted alkyl, aryl and alkylaryl groups having from about 2 toabout 18 carbon atoms. Further, the diamino compound can be synthesizedcontaining a hydrolyzable link such as one or more ester groups toaccelerate the rate of polymer degradation (absorption) in the body. Thefollowing structure exemplifies this concept for hexamethylenediamine:H₂NCH₂CH₂CH₂COOCH₂CH₂NH₂.

In certain embodiments, the polyol comprises 2 to 4 ester groups or 5 to10 ester groups. Suitable polyols have at least two hydroxyl groups. Incertain embodiments, the polyol has three or more hydroxyl groups makingthem crosslinkers.

The Chain-Extender/Crosslinker Component

In certain embodiments, one or more optional chain extenders orcrosslinkers is incorporated in the formation of the absorbableisocyanate-based compositions. In certain embodiments, only a chainextender is present. In other embodiments, both a chain extender and acrosslinker are present. In one embodiment, the one or more chainextenders is a low molecular weight polyhydroxyl- and/orpolyamine-terminated compound having a molecular weight in the range of10 to 500 Daltons and a functionality of at least two. In certainembodiments, the chain extender is a short-chain diol or diamine. In aparticular embodiment, the chain extender or crosslinker is selectedfrom glycerol, 1,4 butanediol, 1,6-hexanediol, diethylene glycol, andcombinations thereof. Chain extenders having a functionality of three ormore than three are also referred to as crosslinkers. In certainembodiments, the compositions of the invention are formed withoutcrosslinkers and the compositions of the invention are not crosslinked.In other embodiments, the compositions of the invention are formed withone or more crosslinkers. The degree of crosslinking can be controlled,for example, by varying the amount of crosslinker present.

In certain embodiments, the chain-extender or crosslinker is present inan isocyanate prepolymer in an amount in the range of about 5% to about80% by weight of the isocyanate prepolymer. In certain embodiments, thechain-extender or crosslinker is present in an amount of from about 5%to 20%, about 20% to 30%, about 30% to 40%, about 40% to 50%, about 50%to 60%, from about 60% to 70%, or from about 70% to 80% by weight of theisocyanate prepolymer.

The chain extender may be degradable or non-degradable. Preferably, atleast one degradable chain extender is used. Suitable degradable chainextenders for use in the present invention are described in U.S. PatentApplication Serial No. 2009/0082540, which is incorporated herein byreference. In one embodiment, the at least one degradable chain extenderis HOCH₂CO₂CH₂CH₂OH or HOCH₂CO₂CH₂CH₂O₂CCH₂OH.

Other suitable chain-extenders or crosslinkers include natural orsynthetic aliphatic polyols. Suitable polydiols for use in the presentinvention include diol or diol repeating units with up to 8 carbonatoms. Non-limiting examples include 1,2-ethanediol (ethylene glycol),1,2-propanediol (propylene glycol), 1,3-propanediol, 1,4-butanediol,1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,4-cyclohexanediol, 1,8-octanediol and combinations thereof.

In other embodiments, the chain extender is a polyol selected frompolyethylene glycol and polypropylene glycol having molecular weights of500-10000 Daltons. Other examples include CASPOL1962 and CASPOL5004. Incertain embodiments the preferred polydiols include polydiols selectedfrom polyethylene glycol and polypropylene glycol with molecular weightsof 500-10000. In some embodiments, the crosslinker is a non-absorbablecrosslinker selected from triethanolamine (TEA), trimethylolpropane, andQUADROL (BASF Corp.). In some embodiments, the chain-extender is anon-degradable chain extender selected from 1,4-butanediol,1,6-hexanediol, and diethylene glycol. The chain-extender or crosslinkermay be present in an isocyanate prepolymer in an amount in the range ofabout 10% to about 80% by weight of the isocyanate prepolymer.

In another embodiment, the dual putty system is able to set and adherein aqueous environments. By nature, the isocyanate component, evencontaining hydrolysable linkages, is essentially hydrophobic and willresist dissolution in aqueous systems. This is true for diamines in thiscontext. It has been found that making the diol more hydrophobic byadding a hydrophobic hydrocarbon-rich residue to a polyol, e.g.,glyceryl-1 or 2-monostearate, a more water resistant system is obtained.A variation of this embodiment involves the substitution of asilicon-based moiety for the hydrocarbon-rich residue although this mayaffect absorbability. Alternatively hydrophobicity and setting rate inaqueous environments can be improved through the use of hydrophobicfillers such as insoluble or weakly soluble aliphatic molecules andsalts thereof, including divalent salts, (eg calcium, magnesium, orzinc) of fatty acids. Also useful are cholesterol and its derivatives,as well as silated derivatives of ceramics or bone (Shimp et al., U.S.Pat. No. 7,270,813) Another embodiment of a water resistant, settable,dual putty system adds a small amount of hydrophobic isocyanate to therelatively hydrophilic polyol component resulting in a water-resistantmixture of polyol containing a minor amount of hydrophobic polyurethaneprepolymer. In one embodiment, the chain extender does not comprise anamino acid group.

Water

In certain embodiments, the compositions of the invention contain noadded water. In some embodiments, the compositions are anhydrous. Incertain embodiments where there is no added water, water maynevertheless be present in small amounts. For example, certaincommercially-available polyols comprise a mixture of the polyol and asmall amount of water. In addition, certain optional particulatematerials as described herein, such as calcium carbonate may comprisebound water. Formulating the compositions in an atmosphere that containsmoisture may also result in the incorporation of water into thecompositions. In certain embodiments of the present invention, thecompositions are prepared under a nitrogen purge that comprises adesired amount of moisture, thereby controlling the water content of thecompositions. In other embodiments, water may be added to thecompositions during the process of their formation from the componentparts. In other embodiments, the compositions are prepared underessentially water-free conditions with anhydrous components such thatthe resulting compositions are essentially anhydrous.

In certain embodiments, water is present in the compositions being madein an amount from at least about 0.01% to about 3% by weight of thecomposition. In certain embodiments, water is present in an amount offrom about 0.05% to 1%, from about 0.05% to 1.5%, from about 0.1% to 1%,from about 0.1% to 1.5%, from about 0.1% to 2%, from about 1% to 2%, orfrom about 2% to 3%.

Particulate Materials

The settable compositions of the invention may contain optionalparticulate materials. In one embodiment, the particulate material is anosteoconductive material. In certain embodiments, the particulatematerial supports or promotes the growth of bone at the applicationsite. In one embodiment, the particulate material is non-resorbable. Incertain embodiments, the mean particle size of the optional particulatematerial is in the micron or submicron range. In one embodiment, themean particle size is from about 0.001 to 0.100 microns, from about0.100 to 5 microns, from about 5 to 100 microns, from about 5 to 500microns, or from about 500 to 2000 microns.

In one embodiment, the optional particulate material is a carbonate orbicarbonate material. In one embodiment, the carbonate or bicarbonatematerial comprises or consists of one or more of calcium carbonate,magnesium carbonate, aluminum carbonate, iron carbonate, zinc carbonate,calcium bicarbonate, and sodium bicarbonate. In one embodiment, theoptional particulate material comprises or consists of bone (e.g.,demineralized bone, bone morphogenetic protein, allograft bone, and/orautogenous bone), calcium phosphate, siliconized calcium phosphate,substituted calcium phosphates (e.g., with magnesium, strontium, orsilicate), calcium pyrophosphate, hydroxyapatite, polymethylmethacrylate, glass-ionomer, absorbable phosphate glass, calciumsulfate, tricalcium phosphate (e.g., beta tricalcium phosphate), or anycombination of the foregoing. Other examples include one or more polyether ether ketones (e.g., PEEK), REPLACE (Cortek, Inc.), EXPANCEL (AkzoNobel). In other embodiments, the particulate material is a ceramic suchas substituted calcium phosphates (e.g, silicate, strontium or magnesiumsubstitution) or a glass such as bioglass. In one embodiment, theparticulate material comprises or consists of one or more of calciumsulfate, calcium phosphosilicate, sodium phosphate, calcium aluminate,calcium phosphate, hydroxyapatite, demineralized bone, or mineralizedbone.

The optional particulate material, when present, may comprise any one ormore of the materials listed in the embodiments above. In oneembodiment, the particulate material, if present in the composition,does not comprise calcium carbonate. In one embodiment, the particulatematerial may be polymeric such as a polyurethane.

In one embodiment, the particulate material is present in an amount offrom about 0.01% to about 10% by weight of the composition. In certainembodiments, the optional particulate material is present in an amountof 0.10% to 10%, 1% to 10%, or 5% to 10%. In other embodiments, theoptional particulate material is present in an amount of from about 10%to about 20% by weight of the composition, or from about 20% to 30%,about 30% to 40%, about 40% to 50%, about 50% to 60%, about 60% to 70%or about 70% to 80% by weight of the composition.

In one embodiment, the particulate additive material is graphene(available from Applied Graphene Materials and Thomas Swan, Ltd.), asingle atomic layer of graphite that is electrically conductive, highlyelastic, is about 100 times stronger than steel and which may be ofvalue improving the quality of tissue healing and new bone stimulation.

Other Optional Additives

The compositions of the invention may also optionally comprise one ormore “cell openers.” Non-limiting examples include ORTOGEL501(Goldschmidt) and X-AIR (Specialty Polymers & Services). In certainembodiments, the cell openers are present in an amount in of from about0.1% to 5% by weight of the composition. In one embodiment, the cellopeners are present in an amount in of from about 1% to 2% or 1% to 3%by weight of the composition. Optional additives can be added to themagnesium based section but for the malonate/cyanoacrylate section, noactive hydrogen atoms can be present including those in water becausethey will initiate polymerization.

The compositions of the invention may also optionally comprise one ormore therapeutic agents. In one embodiment, the one or more therapeuticagents are selected from an anti-cancer agent, an antimicrobial agent,an antibiotic, a local anesthetic or analgesic, a statin and ananti-inflammatory agent. In one embodiment, the antibiotic is selectedfrom a broad spectrum antibiotic, such as gentamicin, clindamycin, anderythromycin, or a gram positive and gram negative family antibioticsuch as an ampicillin and a cephalosporin. In one embodiment, the localanesthetic or analgesic is selected from lidocaine, bupivacaine,tetracaine, and ropivacaine. In one embodiment, the local anesthetic oranalgesic is selected from lidocaine, benzocaine and fentanyl (a potentnon-opioid anesthetic). In one embodiment, the one or moreanti-inflammatory substances is selected from a non-specificanti-inflammatory such as ibuprofen and aspirin, or a COX-2 specificinhibitor such as rofecoxib and celeboxib.

In one embodiment, component A is a putty comprised of a concentratedaqueous solution of a polyanionic polymer, e.g., carboxymethylcellulose,and component B is a putty comprised of a concentrated aqueous solutionof a polycationic polymer. e.g., chitosan, either of which may beoptionally crosslinked. The combined materials are hemostatic whenapplied to a bleeding surface.

In one embodiment, the compositions further comprise one or more of anantioxidant, a colorant, a steroid, calcium stearate, tocopherylacetate, and triacetin. In one embodiment, the antioxidant is selectedfrom IRGANOX 1010 and IRGANOX 1035 (Ciba Geigy), and CYANOX 1790 andCYANOX 2777 (Cytec Industries). In certain embodiments, the antioxidantis present in an amount of from about 0.01% to 0.5% by weight of thecomposition. In one embodiment, the composition comprises one or more ofcalcium stearate, tocopheryl acetate, and triacetin, each present in acomponent putty of the composition in an amount ranging from 0.1 to 5%based upon the weight of the component putty. Non-limiting examples ofcolorants that may be included in the compositions are gentian violet,D&C Violet #2, and D&C Green #6.

In one embodiment, the steroid is a steroid-based compound, such as anintracellular messenger, effective to modulate the rate of tissuegrowth, including bone growth.

In one embodiment, the compositions further comprise one or more growthfactors, for example BMP-2, BMP-7, PDGF, EGF, etc.

EQUIVALENTS

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

What is claimed is:
 1. A plurality of biocompatible, settable componentparts which, upon mixing, react to form a cured final composition atroom or body temperature over a period time, the final compositionoptionally being biodegradable under physiological conditions, whereinthe plurality of component parts consists of two parts, A and B, Acomprising a methylidene malonate ester and a poly(methylidene malonateester) and B comprising poly (methylidenemalonate ester).
 2. Theplurality of claim 1, wherein the component parts are in the form of aputty or paste which is hand-moldable at room temperature.
 3. Theplurality of claim 2, wherein the component parts, upon mixing, remainhand-moldable for a period of time that is from 1 to 20 minutes.
 4. Theplurality of claim 1, further comprising one or more osteopromotiverecombinant proteins selected from the group consisting of bonemorphogenic proteins, platelet derived growth factor, transforminggrowth factor beta, epidermal growth factor, NELL and UCB-I.
 5. Theplurality of claim 1, further comprising 5 to 85 wt, based upon totalweight of the final composition, of a synthetic and/or tissue-derivedparticulate component.
 6. The plurality of claim 5, wherein theparticulate component is porous or nonporous.
 7. The plurality of claim1, wherein the mixed homogenous composition is thermoplastic and can besoftened to return it to a hand-moldable state by applying heatsufficient to warm the composition to a temperature at least higher than40° C., preferably between 40° C. and 100° C.
 8. The plurality of claim1, further comprising an additive selected from one or more oftocopheryl esters, triglycerides, triethylcitrate acetate, and fattyacid esters.
 9. The plurality of claim 1, wherein component A furthercomprises a free radical induced polymerization inhibitor and abase-induced polymerization inhibitor.
 10. The plurality of claim 9,wherein the free radical induced polymerization inhibitor comprises 0.1wt % hydroquinone and the base-induced polymerization inhibitorcomprises 0.5 wt % sulfur dioxide.
 11. The plurality of claim 1, whereincomponent B further comprises one or more additives selected from thegroup consisting of an anhydrous particulate material, a colorant, atherapeutic agent, or a radiopaque agent.
 12. The plurality of claim 11,wherein the therapeutic agent is selected from one or more of ananalgesic, an antimicrobial agent, an anti-inflammatory agent, ananti-coagulant, a statin, and an osteogenic agent.
 13. The plurality ofclaim 1 in which each component of a set of two contains a differentcolorant selected from primary or secondary hues such that when thecolored components are mixed, the colors combine to form a third colorwhich may be used to visually indicate homogeneity of the mixture. 14.The plurality of claim 1 in which the components can be hand mixed tohomogeneity in one minute, three minutes, nine minutes, or twelveminutes.
 15. The plurality of claim 1 in which one or more individualcomponents contains an alkylpyrrolidone.
 16. The plurality of claim 1 inwhich 0.1-5% graphene is added as a particulate component.